Antimicrobial compounds are compounds capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria, protozoa, mycoplasma, yeast, and fungi. The mechanisms by which antimicrobial compounds act vary. However, they are generally believed to function in one or more of the following ways: by inhibiting cell wall synthesis or repair; by altering cell wall permeability; by inhibiting protein synthesis; or by inhibiting synthesis of nucleic acids. For example, beta-lactam antibacterials inhibit the essential penicillin binding proteins (PBPs) in bacteria, which are responsible for cell wall synthesis. Quinolones act, at least in part, by inhibiting synthesis of DNA, thus preventing the cell from replicating.
Many attempts to produce improved antimicrobials yield equivocal results. Indeed, few antimicrobials are produced that are truly clinically acceptable in terms of their spectrum of antimicrobial activity, avoidance of microbial resistance, and pharmacology. There is a continuing need for broad-spectrum antimicrobials, and a particular need for antimicrobials effective against resistant microbes.
Pathogenic bacteria are known to acquire resistance via several distinct mechanisms including inactivation of the antibiotic by bacterial enzymes (e.g., beta-lactamases that hydrolyze penicillin and cephalosporins); removal of the antibiotic using efflux pumps; modification of the target of the antibiotic via mutation and genetic recombination (e.g., penicillin-resistance in Neiserria gonorrhea); and acquisition of a readily transferable gene from an external source to create a resistant target (e.g., methicillin-resistance in Staphylococcus aureus). There are certain Gram-positive pathogens, such as vancomycin-resistant Enterococcus faecium, which are resistant to virtually all commercially available antibiotics.
Resistant organisms of particular note include methicillin-resistant and vancomycin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, fluoroquinolone-resistant E. coli, cephalosporin-resistant aerobic gram-negative rods and imipenem-resistant Pseudomonas aeruginosa. These organisms are significant causes of nosocomial infections and are clearly associated with increasing morbidity and mortality. The increasing numbers of elderly and immunocompromised patients are particularly at risk for infection with these pathogens. Therefore, there is a large unmet medical need for the development of new antimicrobial agents. In recent years Methicillin Resistant Staphylococcus Aureus (MRSA) infections have become more common, particularly in institutional and hospital settings. Up to 60% of staphylococcus infections are attributable to methicillin resistant strains in some parts of the United States. Some MRSA strains are now resistant to both Vancomycin and Gentamicin, drugs once considered the last defense against staphylococcus infections. Thus, there is a particularly urgent need for drugs effective against MRSA strains.
Quinoline compounds effective against methicillan susceptible Staphylococcus aureus have been previously identified. For example, see Japanese laid-open publication no. 03-223289. JP 03-223289 discusses compounds having activity against MSSA rather than MRSA. Generally quinolone and isothiazoloquinolone compounds are 32-128 fold less active against MRSA than MSSA. Thus one of skill in the art would not expect compounds discussed in JP 03-223289 to be effective against MRSA. The inventors have unexpectedly identified a class of hydroxylthienoquinolones that are only 4-8 fold less active against MRSA than MSSA, as measured by MIC assay, and thus quite useful for treating MRSA infections. The unexplained improved MSSA/MRSA MIC ratio also suggests an alternate mode of action or binding at the active site for the newly discovered compounds.
The present invention fulfills the need for drugs effective against MRSA, and provides further related advantages.